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The X-ray crystal structures of two new (trifluoroacetyl)dipeptide
p-(trifluoromethyl)anilide (TFA-dipeptide-TFM) inhibitors complexed to porcine
pancreatic elastase are presented. TFA-Val-Ala-TFM and TFA-Phe-Ala-TFM both bind
to elastase with the TFA group in the S1 subsite, Val or Phe in the S2 subsite,
Ala in the S3 subsite, and the TFM group in the S4 subsite. Five other
TFA-dipeptide-anilide/elastase crystal structures are available (two
TFA-X-Ala-p-(trifluoromethyl)anilide, X = Lys, Leu, and three
TFA-Lys-X-p-isopropylanilide, X = Pro, Leu, Phe). The four inhibitors with the
trifluoromethyl substituent on the anilide ring bind in a single mode to
elastase, whereas superposition of the three inhibitors with the isopropyl
substituent on the anilide ring show three different modes of binding to the
protein [Mattos, C., et al. (1994) Nature Struct. Biol. 1, 55-58]. The seven
structures are taken together in a detailed analysis of the active site of
porcine pancreatic elastase. The inhibition constants for the inhibitors are
used in combination with the crystal structures to understand the specificity of
the different elastase subsites.
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